Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens

Shaela Wright, Xujie Zhao, Wojciech Rosikiewicz, Shelby Mryncza, Judith Hyle, Wenjie Qi, Zhenling Liu, Siqi Yi, Yong Cheng, Beisi Xu and Chunliang Li ()
Additional contact information
Shaela Wright: St. Jude Children’s Research Hospital
Xujie Zhao: St. Jude Children’s Research Hospital
Wojciech Rosikiewicz: St. Jude Children’s Research Hospital
Shelby Mryncza: Rhodes College
Judith Hyle: St. Jude Children’s Research Hospital
Wenjie Qi: St. Jude Children’s Research Hospital
Zhenling Liu: St. Jude Children’s Research Hospital
Siqi Yi: St. Jude Children’s Research Hospital
Yong Cheng: St. Jude Children’s Research Hospital
Beisi Xu: St. Jude Children’s Research Hospital
Chunliang Li: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq. Integrative data analysis identifies reproducible noncoding hits, including those located in the distal enhancer of FLT3 and intron of CDK6. The Cas9-editing and dCas9-KRAB silencing of the HOXA9-bound sites significantly reduce corresponding gene transcription and impair cell proliferation in vitro, and in vivo by transplantation into NSG female mice. In addition, RNA-seq, Q-PCR analysis, chromatin accessibility change, and chromatin conformation evaluation uncover the noncoding regulation mechanism of HOXA9 and its functional downstream genes. In summary, our work improves our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43264-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43264-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43264-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().